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Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

PD-L1 PET imaging allows for the whole body measuring its expression across primary and metastatic tumors and visualizing its spatiotemporal dynamics before, during, and after treatment. In this study, we reported a novel 18F-labeled D-peptide antagonist, 18F-NOTA-NF12, for PET imaging of PD-L1 status in preclinical and first-in-human studies.

Methods

Manual and automatic radiosynthesis of 18F-NOTA-NF12 was performed. Cell uptake and binding assays were completed in MC38, H1975, and A549 cell lines. The capacity for imaging of PD-L1 status, biodistribution, and pharmacokinetics were investigated in preclinical models. The PD-L1 status was verified by western blotting, immunohistochemistry/fluorescence, and flow cytometry. The safety, radiation dosimetry, biodistribution, and PD-L1 imaging potential were evaluated in healthy volunteers and patients.

Results

The radiosynthesis of 18F-NOTA-NF12 was achieved via manual and automatic methods with radiochemical yields of 41.7 ± 10.2 % and 70.6 ± 4.2 %, respectively. In vitro binding assays demonstrated high specificity and affinity with an IC50 of 78.35 nM and KD of 85.08 nM. The MC38 and H1975 tumors were clearly visualized with the optimized tumor-to-muscle ratios of 5.36 ± 1.17 and 7.13 ± 1.78 at 60 min after injection. Gemcitabine- and selumetinib-induced modulation of PD-L1 dynamics was monitored by 18F-NOTA-NF12. The tumor uptake correlated well with their PD-L1 expression. 18F-NOTA-NF12 exhibited renal excretion and rapid clearance from blood and other non-specific organs, contributing to high contrast imaging in the clinical time frame. In NSCLC and esophageal cancer patients, the specificity of 18F-NOTA-NF12 for PD-L1 imaging was confirmed. The 18F-NOTA-NF12 PET/CT and 18F-FDG PET/CT had equivalent findings in patients with high PD-L1 expression.

Conclusion

18F-NOTA-NF12 was developed successfully as a PD-L1-specific tracer with promising results in preclinical and first-in-human trials, which support the further validation of 18F-NOTA-NF12 for PET imaging of PD-L1 status in clinical settings.

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Acknowledgements

The authors would like to acknowledge Dr. Zhiguo Liu (Shandong Cancer Hospital) for the design, assembly, and optimization of the ChelationLab@Al18F automatic platform, Dr. Chao Chen (Xiangya Hospital) for flow cytometry analysis, and Dr. Xin Yan (Sun Yat-sen University) for molecular docking.

Funding

This study was financially supported by the National Natural Science Foundation of China (91859207, 81801762, 81771873, and 91959122), the Joint Fund of National Natural Science Foundation of China - China National Nuclear Corporation for Nuclear Technology Innovation (U1967222), and the Natural Science Foundation of Hunan Province of China (2020JJ5956).

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Author notes

  1. Ming Zhou, Xiaobo Wang, and Bei Chen contributed equally to this work and are first authors.

Authors and Affiliations

  1. Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China

    Ming Zhou, Bei Chen, Shijun Xiang, Wanqian Rao, Xiaoqin Yin & Shuo Hu

  2. Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, 4221-116 Xiang’an South Rd., Xiamen, 361102, China

    Xiaobo Wang, Zhe Zhang, Huanhuan Liu, Jianyang Fang & Xianzhong Zhang

  3. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China

    Pengbo Deng

  4. National Clinical Research Center for Geriatric Disorders (Xiangya), Changsha, China

    Shuo Hu

  5. Key Laboratory of Biological, Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, 87 Xiangya Rd., Changsha, 410008, China

    Shuo Hu

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  1. Ming Zhou
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Contributions

Design and supervision: SH and XZ; methodology: XW, MZ, and BC; data collection and analysis: XW, MZ, BC, SX, WR, XY, ZZ, HL, and JF; patient recruitment, PET scan, and analysis: SH, PD, MZ, XW, and BC; manuscript writing, review, and editing: XW, SH, and XZ.

Corresponding authors

Correspondence to Xianzhong Zhang or Shuo Hu.

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Ethics approval

All clinical studies were approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (No. 202106115). All animal studies were performed according to the guidelines of the Animal Care Committee of Central South University.

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The authors declare no competing interests.

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This article is part of the Topical Collection on Preclinical Imaging

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Zhou, M., Wang, X., Chen, B. et al. Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET. Eur J Nucl Med Mol Imaging 49, 4312–4324 (2022). https://doi.org/10.1007/s00259-022-05876-9

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  • DOI: https://doi.org/10.1007/s00259-022-05876-9

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